Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling

Autores
Dalton, George; An, Sung-Wan; Al-Juboori, Saif I.; Nischan, Nicole; Yoon, Joonho; Dobrinskikh, Evgenia; Hilgemann, Donald W.; Xie, Jian; Luby-Phelps, Kate; Kohler, Jennifer J.; Birnbaumer, Lutz; Huang, Chou-Long
Año de publicación
2017
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Soluble klotho, the shed ectodomain of the antiaging membrane protein α-klotho, is a pleiotropic endocrine/paracrine factor with no known receptors and poorly understood mechanism of action. Soluble klotho down-regulates growth factor-driven PI3K signaling, contributing to extension of lifespan, cardioprotection, and tumor inhibition. Here we show that soluble klotho binds membrane lipid rafts. Klotho binding to rafts alters lipid organization, decreases membrane´s propensity to form large ordered domains for endocytosis, and down-regulates raft-dependent PI3K/Akt signaling. We identify α2-3-sialyllactose present in the glycan of monosialogangliosides as targets of soluble klotho. α2-3-Sialyllactose is a common motif of glycans. To explain why klotho preferentially targets lipid rafts we show that clustering of gangliosides in lipid rafts is important. In vivo, raft-dependent PI3K signaling is up-regulated in klotho-deficient mouse hearts vs. wild-type hearts. Our results identify ganglioside-enriched lipid rafts to be receptors that mediate soluble klotho regulation of PI3K signaling. Targeting sialic acids may be a general mechanism for pleiotropic actions of soluble klotho.
Fil: Dalton, George. University of Texas Southwestern Medical Center; Estados Unidos
Fil: An, Sung-Wan. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Al-Juboori, Saif I.. University of Colorado Denver; Estados Unidos
Fil: Nischan, Nicole. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Yoon, Joonho. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Dobrinskikh, Evgenia. University of Colorado Denver; Estados Unidos
Fil: Hilgemann, Donald W.. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Xie, Jian. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Luby-Phelps, Kate. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Kohler, Jennifer J.. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. National Institute of Environmental Health Sciences; Estados Unidos. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Ciencias Médicas; Argentina
Fil: Huang, Chou-Long. University of Texas Southwestern Medical Center; Estados Unidos
Materia
GANGLIOSIDES
LIPID RAFTS
SIALIC ACIDS
SOLUBLE KLOTHO
TRPC6
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/47856
Acceder
id CONICETDig_8da6544dff16b905fabd5aa2ff8a62b8
oai_identifier_str oai:ri.conicet.gov.ar:11336/47856
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signalingDalton, GeorgeAn, Sung-WanAl-Juboori, Saif I.Nischan, NicoleYoon, JoonhoDobrinskikh, EvgeniaHilgemann, Donald W.Xie, JianLuby-Phelps, KateKohler, Jennifer J.Birnbaumer, LutzHuang, Chou-LongGANGLIOSIDESLIPID RAFTSSIALIC ACIDSSOLUBLE KLOTHOTRPC6https://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Soluble klotho, the shed ectodomain of the antiaging membrane protein α-klotho, is a pleiotropic endocrine/paracrine factor with no known receptors and poorly understood mechanism of action. Soluble klotho down-regulates growth factor-driven PI3K signaling, contributing to extension of lifespan, cardioprotection, and tumor inhibition. Here we show that soluble klotho binds membrane lipid rafts. Klotho binding to rafts alters lipid organization, decreases membrane´s propensity to form large ordered domains for endocytosis, and down-regulates raft-dependent PI3K/Akt signaling. We identify α2-3-sialyllactose present in the glycan of monosialogangliosides as targets of soluble klotho. α2-3-Sialyllactose is a common motif of glycans. To explain why klotho preferentially targets lipid rafts we show that clustering of gangliosides in lipid rafts is important. In vivo, raft-dependent PI3K signaling is up-regulated in klotho-deficient mouse hearts vs. wild-type hearts. Our results identify ganglioside-enriched lipid rafts to be receptors that mediate soluble klotho regulation of PI3K signaling. Targeting sialic acids may be a general mechanism for pleiotropic actions of soluble klotho.Fil: Dalton, George. University of Texas Southwestern Medical Center; Estados UnidosFil: An, Sung-Wan. University of Texas Southwestern Medical Center; Estados UnidosFil: Al-Juboori, Saif I.. University of Colorado Denver; Estados UnidosFil: Nischan, Nicole. University of Texas Southwestern Medical Center; Estados UnidosFil: Yoon, Joonho. University of Texas Southwestern Medical Center; Estados UnidosFil: Dobrinskikh, Evgenia. University of Colorado Denver; Estados UnidosFil: Hilgemann, Donald W.. University of Texas Southwestern Medical Center; Estados UnidosFil: Xie, Jian. University of Texas Southwestern Medical Center; Estados UnidosFil: Luby-Phelps, Kate. University of Texas Southwestern Medical Center; Estados UnidosFil: Kohler, Jennifer J.. University of Texas Southwestern Medical Center; Estados UnidosFil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. National Institute of Environmental Health Sciences; Estados Unidos. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Ciencias Médicas; ArgentinaFil: Huang, Chou-Long. University of Texas Southwestern Medical Center; Estados UnidosNational Academy of Sciences2017-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/47856Dalton, George; An, Sung-Wan; Al-Juboori, Saif I.; Nischan, Nicole; Yoon, Joonho; et al.; Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 114; 4; 1-2017; 752-7570027-8424CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1620301114info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/114/4/752info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:01:58Zoai:ri.conicet.gov.ar:11336/47856instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:01:59.024CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
title Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
spellingShingle Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
Dalton, George
GANGLIOSIDES
LIPID RAFTS
SIALIC ACIDS
SOLUBLE KLOTHO
TRPC6
title_short Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
title_full Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
title_fullStr Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
title_full_unstemmed Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
title_sort Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling
dc.creator.none.fl_str_mv Dalton, George
An, Sung-Wan
Al-Juboori, Saif I.
Nischan, Nicole
Yoon, Joonho
Dobrinskikh, Evgenia
Hilgemann, Donald W.
Xie, Jian
Luby-Phelps, Kate
Kohler, Jennifer J.
Birnbaumer, Lutz
Huang, Chou-Long
author Dalton, George
author_facet Dalton, George
An, Sung-Wan
Al-Juboori, Saif I.
Nischan, Nicole
Yoon, Joonho
Dobrinskikh, Evgenia
Hilgemann, Donald W.
Xie, Jian
Luby-Phelps, Kate
Kohler, Jennifer J.
Birnbaumer, Lutz
Huang, Chou-Long
author_role author
author2 An, Sung-Wan
Al-Juboori, Saif I.
Nischan, Nicole
Yoon, Joonho
Dobrinskikh, Evgenia
Hilgemann, Donald W.
Xie, Jian
Luby-Phelps, Kate
Kohler, Jennifer J.
Birnbaumer, Lutz
Huang, Chou-Long
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv GANGLIOSIDES
LIPID RAFTS
SIALIC ACIDS
SOLUBLE KLOTHO
TRPC6
topic GANGLIOSIDES
LIPID RAFTS
SIALIC ACIDS
SOLUBLE KLOTHO
TRPC6
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Soluble klotho, the shed ectodomain of the antiaging membrane protein α-klotho, is a pleiotropic endocrine/paracrine factor with no known receptors and poorly understood mechanism of action. Soluble klotho down-regulates growth factor-driven PI3K signaling, contributing to extension of lifespan, cardioprotection, and tumor inhibition. Here we show that soluble klotho binds membrane lipid rafts. Klotho binding to rafts alters lipid organization, decreases membrane´s propensity to form large ordered domains for endocytosis, and down-regulates raft-dependent PI3K/Akt signaling. We identify α2-3-sialyllactose present in the glycan of monosialogangliosides as targets of soluble klotho. α2-3-Sialyllactose is a common motif of glycans. To explain why klotho preferentially targets lipid rafts we show that clustering of gangliosides in lipid rafts is important. In vivo, raft-dependent PI3K signaling is up-regulated in klotho-deficient mouse hearts vs. wild-type hearts. Our results identify ganglioside-enriched lipid rafts to be receptors that mediate soluble klotho regulation of PI3K signaling. Targeting sialic acids may be a general mechanism for pleiotropic actions of soluble klotho.
Fil: Dalton, George. University of Texas Southwestern Medical Center; Estados Unidos
Fil: An, Sung-Wan. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Al-Juboori, Saif I.. University of Colorado Denver; Estados Unidos
Fil: Nischan, Nicole. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Yoon, Joonho. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Dobrinskikh, Evgenia. University of Colorado Denver; Estados Unidos
Fil: Hilgemann, Donald W.. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Xie, Jian. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Luby-Phelps, Kate. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Kohler, Jennifer J.. University of Texas Southwestern Medical Center; Estados Unidos
Fil: Birnbaumer, Lutz. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. National Institute of Environmental Health Sciences; Estados Unidos. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Facultad de Ciencias Médicas; Argentina
Fil: Huang, Chou-Long. University of Texas Southwestern Medical Center; Estados Unidos
description Soluble klotho, the shed ectodomain of the antiaging membrane protein α-klotho, is a pleiotropic endocrine/paracrine factor with no known receptors and poorly understood mechanism of action. Soluble klotho down-regulates growth factor-driven PI3K signaling, contributing to extension of lifespan, cardioprotection, and tumor inhibition. Here we show that soluble klotho binds membrane lipid rafts. Klotho binding to rafts alters lipid organization, decreases membrane´s propensity to form large ordered domains for endocytosis, and down-regulates raft-dependent PI3K/Akt signaling. We identify α2-3-sialyllactose present in the glycan of monosialogangliosides as targets of soluble klotho. α2-3-Sialyllactose is a common motif of glycans. To explain why klotho preferentially targets lipid rafts we show that clustering of gangliosides in lipid rafts is important. In vivo, raft-dependent PI3K signaling is up-regulated in klotho-deficient mouse hearts vs. wild-type hearts. Our results identify ganglioside-enriched lipid rafts to be receptors that mediate soluble klotho regulation of PI3K signaling. Targeting sialic acids may be a general mechanism for pleiotropic actions of soluble klotho.
publishDate 2017
dc.date.none.fl_str_mv 2017-01
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/47856
Dalton, George; An, Sung-Wan; Al-Juboori, Saif I.; Nischan, Nicole; Yoon, Joonho; et al.; Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 114; 4; 1-2017; 752-757
0027-8424
CONICET Digital
CONICET
url http://hdl.handle.net/11336/47856
identifier_str_mv Dalton, George; An, Sung-Wan; Al-Juboori, Saif I.; Nischan, Nicole; Yoon, Joonho; et al.; Soluble klotho binds monosialoganglioside to regulate membrane microdomains and growth factor signaling; National Academy of Sciences; Proceedings of the National Academy of Sciences of The United States of America; 114; 4; 1-2017; 752-757
0027-8424
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1073/pnas.1620301114
info:eu-repo/semantics/altIdentifier/url/http://www.pnas.org/content/114/4/752
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv National Academy of Sciences
publisher.none.fl_str_mv National Academy of Sciences
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842269727935692800
score 13.13397

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